1. The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia
A Y Deutch J Neural Transm Suppl. 1992;36:61-89. doi: 10.1007/978-3-7091-9211-5_5.
A recent hypothesis of the pathogenesis of schizophrenia posits a developmentally-specific dysfunction of the dopaminergic innervation of the prefrontal cortex (PFC; Weinberger, 1987; Berman and Weinberger, 1990). It has been difficult to reconcile this hypothesis with the observation that all clinically effective antipsychotic drugs used for the treatment of schizophrenia block dopamine D2 receptors (see Deutch et al., 1991a). A resolution between the suggestion of functional dopamine (DA) "depletion" in the PFC and enhanced subcortical DA function was offered by studies of Carter, Pycock, and associates (Carter and Pycock, 1980; Pycock et al., 1980a, b). These investigators reported that depletion of DA in the rat PFC enhanced DA utilization in subcortical sites such as the nucleus accumbens septi (NAS) and striatum. Thus, a functional deficit in DA neurotransmission in the PFC would increase subcortical DA turnover, and the D2 receptor blockade induced by antipsychotic drugs would counteract the increase in dopaminergic tone in subcortical sites. This hypothesis has been particularly influential because it incorporates both an explanation for negative symptoms, which are thought to reflect cortical dysfunction (a derangement in DA transmission in the PFC), and the efficacy of antipsychotic drugs in the treatment of positive symptoms (arising from increases in subcortical DA tone). As attractive as this hypothesis has been, the physiological underpinnings that subserve such system interactions have remained elusive. Pycock, Carter, and colleagues (Carter and Pycock, 1980; Pycock et al., 1980a, b) reported that 6-hydroxydopamine (6-OHDA) lesions of the PFC increase DA levels and DA turnover in the striatum; certain aspects of their findings have been confirmed (Martin-Iversen et al., 1986; Leccese and Lyness, 1987; Haroutounian et al., 1988). However, other groups have been unable to confirm either the biochemical or behavioral findings of Pycock and associates (Joyce et al., 1983; Oades et al., 1986; Deutch et al., 1990). Moreover, Pycock and colleagues did not observe consistent effects of PFC DA deafferentation on various indices of subcortical DA function (Carter and Pycock, 1980; Pycock et al., 1980a, b). In light of the importance that such DA system interactions may have in the pathogenesis of schizophrenia, we have reinvestigated the effects of cortical DA lesions on subcortical DA function.
2. A life of cycles
Jonathan Pycock Vet Rec. 2015 Mar 7;176(10):i-ii. doi: 10.1136/vr.h1199.
Jonathan Pycock is one of three equine claims consultants with the Veterinary Defence Society. His career in equine reproduction, and lecturing on the same topic, has given him the opportunity to work and travel widely, and ensure his work/life balance stays in sync.
3. SLCO1B1 variants and statin-induced myopathy--a genomewide study
SEARCH Collaborative Group, E Link, S Parish, J Armitage, L Bowman, S Heath, F Matsuda, I Gut, M Lathrop, R Collins N Engl J Med. 2008 Aug 21;359(8):789-99. doi: 10.1056/NEJMoa0801936. Epub 2008 Jul 23.
Background: Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. Methods: We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. Results: The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. Conclusions: We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)
